1,5-benzodiazepines and process for preparing them

ABSTRACT

Dialkylphosphinylalkylene-substituted 1,5-benzodiazepines useful as medicaments in the treatment of psychic diseases are obtainable by reacting the corresponding benzodiazepines with a dialkyl-phosphinylalkyl halide or by reacting a 2-dialkylphosphinylalkylaminodiphenylamine with a malonic acid dihalide or alkylmalonic acid dihalide.

United States Patent H 1 [1 11 3,718,645 Kuch et a]. 1 Feb. 27 1973 eerences ited 1,5 BENZODIAZEPINES AND PROCESS [56] R f C FOR PREPARINGTHEM OTHER PUBLICATIONS [75] Inventors: Heinz Kuch, Frankfurt am Mam;

' Irmgard Hoffman, Bad Soden, ROSSI et aL, A Chimicce E LIndustna (May1969) Taunus, of Germany V01. 51, N0. 5 pages [73] Assignee: FarbwerkeHoechst Aktiengesellprimary Examiner john Randolph schaff vormals Musterf' Assistant Examiner-Robert T. Bond Bnmmg Frankfurt amAttorney--Curtis, Morris & Safford many [22] Filed: May 6, 1971 [57]ABSTRACT [21] AppLNoJ 140,978 Dialkylphosphinylaikylene-substituted 1,5-

benzodiazepines useful as medicaments in the treatment of psychicdiseases are obtainable by reacting [30] Foreign Apphcguon Pnomy Datathe corresponding benzodiazepines with a dialkyl- April 15, 1970 Germany..P 21 18 262.7 P p y y halide or by reacting a -p a Iphinylalkylaminodiphenylamine with a malonic acid 52 US. Cl. ..260/239.3B, 424/244 dihalide or alkylmalonic acid dihalide [51] Int, Cl. ..C07d53/04 [58] Field of Search ..260/239.3 B 3 Drawmgs 1,5-BENZODIAZEPINESAND PROCESS FOR PREPARING THEM The present invention relates to1,5-benzodiazepines and to a process for preparing them.

More particularly, the invention relates to new benzodiazepinederivatives of the general formula l in which R represents an alkylgroup having one to three carbon atoms, R and R which may be identicalor different, represent a hydrogen atom or a halogen atom, thetrifluoromethyl or nitro group, or an alkoxy group having one to twocarbon atoms, R represents a hydrogen atom or an alkyl group having oneto three carbon atoms, and n represents a number from 1 to 3.

The invention furthermore provides a process for preparing theabove-specified compounds of the formula I, which comprises a. reactingin the presence of metallizing agents 1,5-

benzodiazepine derivatives of the general formula II in which R R, and Rhave the meanings given above, with dialkyl-phosphinylalkyl compounds ofthe general formula III in which R and n have the meanings given aboveand X represents a halogen atom or an alkane-sulfonic 8Cld oraryl-sulfonic acid radical, or

b. reacting a 2amino-diphenylamin'o derivative of 2,4-dione,

in which R, R R and n have the meanings given above, with a malonic aciddihalide or alkyl-malonic acid dihalide, optionally while usingacid-binding agents.

As benzodiazepines of the general formula H which may be used asstarting substances in method a) of the process of the invention andwhich may be prepared according to known processes (cf. DOS No. l 668634 and DOS No. l 670 (published German Applications, there may bementioned:

5-phenyi-l ,2,4,5-tetrahydro-3ll*l-l ,S-benzodiazepine-5-(4'-methoxyphenyl)-1,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione, 6-chl0ro-5-phenyll,2,4,5-tetrahydro-3H- l ,5-benzodiazepine-2,4-dione, 7-fluoro-5-phenyl-l,2,4,5-tetrahydro-3H-1,5- benzodiazepine-2,4-dione,7-chloro-5-phenyl-l,2,4,5- tetrahydro-SlH-l ,5-benzodiazepine-2,4-dione,7- chloro-5-(2'-fluorophenyl)-l ,2,4,5-tetrahydro-3H-l ,5-benzodiazepine-2,4-dione, 7-chloro-5-(2'-chlorophenyl)- 1 ,2,4,5-tetrahydr0-3H-l ,5-benzodiazepine-2,4- dione, 7-Bromo-5-phenyl-l,2,4,5-tetrahydro-3H-l ,5- benzodiazepine-2,4-dione,5-phenyl-7-trifluoromethyll ,2,4,5-tetrahydro-3l-l-l,5-benzodiazepine-2,4-dione, 7 nitr0-5-phenyl-l ,2,4,5-tetrahydro-3H-l,5- benzodiazepine-2,4-dione, 7-methoxy-5-phenyl-i ,2,4,5-tetrahydro-3l-l-l ,5-benzodiazepine-2,4-dione, 7- methoxy-S-phenyl-l,2,4,5-tetrahydro-3l-l-l ,5- benzodiazepine-2,4-di0ne,S-methoxy-S-phenyl-l ,2,4,5 -tetrahydro-3H-l ,5-benzodiazepine-2,4-dione, 7- chloro-3-methyl-5-phenyl-l,2,4,5-tetrahydro-3H-l ,5- benzodiazepine-2,4-dione and 7-chloro-5-(2'chlorophenyl )-3 -methyl-l ,2,4,5-tetrahydro-3H-l ,5benzodiazepine-2,4-clione.

The corresponding dialkyl-phosphinylalkyl compounds of the generalformule ill, for example chloromethyl-dimethyl-phosphinc-oxide,bromomethyl-dimethyl-phosphine-oxide, 2-chloroethyl-dimethyl-phosphine-oxide, v 3-chloroporoyl-dimethyl-phosphine oxide,iodomethyldimethyl-phosphine-oxide, methane-sulfonicaciddimethyl-phosphinylmethyl ester, p-toluenesulfonicacid-dimethylphosphinylmethyl ester are likewise obtained according toknown processes, also the corresponding derivatives of the abovementioned ,com-

pounds in which the term dimethyl is replaced by diethyl, dipropyl" ordi-isopropyl.

The reaction according to method (a)of the process of the invention isgenerally carried out by converting at first a benzodiazepine of thegeneral formula ll with the aid of a metallizing agent into-thecorresponding metal compound and reacting the latter,preferably in thesame reaction vessel, with a dialkyl-phosphinylalkyl compound of thegeneral formula lll. Under circumstances, it may also be of advantage toreverse this order and to add slowly, in small portions, the alkalimetal compound to a mixture of the benzodiazepine with thedialkyl-phosphinyl-alltyl compound. Finally, the benzodiazepinesprepared according to DOS No. l 670 190" (published German application)by alkaline cyclization of correspondingN-(Z-aminophenyl)-N-phenyl-malonic acid alkyl ester amides of thegeneral formula II can also be reacted, without previous isolation, witha dialkyl-phosphinyl-alkyl derivative of the general formula ill. 5 I

The metallizing agents used for the reaction are the usual, preferablyalkali metal or alkaline earth metal hydrides, for example sodiumhydride, calcium hydride, alkali metal amides such as lithium amide orsodium amide and alkali metal alcoholates such as sodium methylate andsodium ethylate or potassium tert. butylate.

As solvents, there may be used in particular inert solvents, for examplearomatic hydrocarbons such as benzene, toluene, xylene, ethers such astetrahydrofurane or dioxane, tertiary amides such as dimethylformamide,dimethylacetamide, furthermore acetonitrile, as well as, in the casealkali metal alcoholates are used, also the corresponding alcohols.

According to the reactivity of the phosphorus component, the reactionaccording to the invention is carried out at temperatures in the rangeof from C to 200 C, preferably between 20 and 160 C. Depending on thetemperature used and on the reactivity of the components, the reactiontimes can be varied within wide limits.

The reaction according to method (b) of the process of the invention iscarried out preferably in a suitable inert solvent, for example toluene,xylene, tetrahydrofurane, dioxane or dimethylformamide at temperaturesin the range from 20 C. to the boiling temperatures of the respectivesolvent used. The addition of an acid-binding agent, for example atertiary organic base such as pyridine or triethylamine is in generalparticularly advantageous.

As the final products which may be obtained according to the process ofthe invention, the following compounds may be mentioned:

l-(dimethylphosphinylmethyl )--phenyl-l ,2,4,5- tetrahydro-3l-l- 1,5-benzodiazepine-2,4-dione,(dimethylphosphinylmethyl)-5-(4'-methoxyphenyl)- 1,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione, 6-chlorol dimethylphosphinylmethyl )-5-phenyl- 1 ,2,4 ,5 -tetrahydro-3I-l-l ,5-benzodiaziepine-2,4-dione,l-(dimethylphosphinylm ethyl )-7 -fluoro-5 -phenyl-1,2,4,5-tetrahydro-3H-1,5-benzodiazepine-2,4-dione, 7-chloroldimethylphosphinylmethyl )-5 -phenyl- 1,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione, 7-chloro- 1 dim ethylphosphinylpropyl)-5-phenyl- 1,2,4,5-tetrahydro-3H-l ,5-benzodiazepine-2,4-dione,7-chloro-1-(diethylphosphinylmethyl)-5-phenyll,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione, 7-chloro- 1di-n-propylphosphinylmethyl)-5-( 2 fluorophenyl)-l,2,4,5-tetrahydro-3H-1,5- benzodiazepine-2,4-dione,7-chloro-l-(dimethylphosphinylmethyl)-5-(2 '-chlorophenyl )-1,2,4,5-tetrahydro- 3H-1,5-benzodiazepine-2,4-dione, 7-bromol(dimethylphosphinylmethyl)-5-phenyl-l ,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione,l-(dimethylphosphinylmethyl)-5-phenyl-7-trifluoromethyll,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione,1-(dimethylphosphinylmethyl)-7-nitro-5-phenyll,2,4,5-tetrahydro-3H-l,S-benzodiazepine-Z,4-dione,1-(dimethylphosphinylmethyl)-7-methoxy-5-phenyll,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione, l-( dimethylphosphinylmethyl)-8-methoxy-5-phenyll,2,4,5-tetrahydro-3H-1,5-benzodiazepine-2,4-dione,7-chloro-l-(dimethylphosphinylmethyl)-3-methyl-5- phenyl-l,2,4,5-tetrahydro-3H-l ,5-benzodiazepine-2,4- 65 The new compounds ofthe general formula I posses valuable pharmacological properties,especially a centrally depressive, tranquillizing, relaxing,narcosis-prolonging and anti-convulsive action and a very low toxicity.Compared with benzodiazepines of similar structure, which however do notcontain the dialkyl-phosphinylalkyl group, the compounds of theinvention in addition have the advantage of being better soluble inwater which makes them suitable especially also for parenteralapplication.

The compounds of the invention are suitable as medicaments in thetreatment of psychic diseases, for example depressions, psychoneuroses,ill-humors, conditions of fear and tension, of neurotic and psychoticgenesis.

The compounds of the invention may be administered in the form oftablets, dragees, capsules, suppositoires or in the form of solutions,suspension or emulsions. These pharmaceutical preparations, which aremanufactured according to the usual galenical methods, may contain inaddition to the active substance also the usual adjuvants and excipientsand/or other therapeutically valuable substances, which do not reactwith the active substances of the invention. They may be sterilizedand/or combined with stabilizers.

The following Examples illustrate the invention:

EXAMPLE 1 l-(Dimethylphosphinylmethyl)-5-phenyl- 1 ,2,4,5-tetrahydro-3l-l-1,5-benzodiazepine-2,4-dione 12.6 g (0.05 mole) of5-phenyl-1,2,4,5-tetrahydro-3 l-l-l,5-benzodiazepine-2,4-dione weredissolved in 350 ml of dimethylformamide and to this solution, 2.5 g ofsodium hydride (about percent strength in paraffin oil) were adifled inportions, at 10 20 C, while stirring, whereupon the sodium compoundprecipitated in the form of a thick crystal magma. Then, 6.5 g ofchloromethyl-dimethyl-phosphine-oxide and 0.2 g of sodium iodide wereadded and the reaction mixture was heated for 3 hours to 120 130 C.After cooling, the content of the flask was filtered and the filtratewas concentrated under reduced pressure. The crude l-(dimethylphosphinylmethyl)-5-phenyl-1,2,4,5-tetrahydro-3H-l,5-benzodiazepine2,4-dione could be purified byrecrystallization from a mixture of chloroform and petroleum ether(boiling point C) or toluene and methanol with the use of charcoal; 13.0g (76 percent of the theory) of colorless crystals melting at 253 255 Cwere obtained.

EXAMPLE 27-Chloro-l-(dimethylphosphinylmethyl)-5-phenyll,2,4,5-tetrahydro-3H-l,5-benzodiazepine-2,4-dione a. 5 g of sodium hydride (about 50 percentstrength in paraffin oil) was added portionwise, while stirring andcooling with ice, to a suspension of 28.7 g (0.1 mole) of7-chloro-5-phenyl-l ,2,4,5-tetrahydro-3H-l ,5- benzodiazepine-2,4-dionein 300 ml of dimethylformamide and the whole was tirred for 30 minutes.After addition of 13.0 g of chloromethyl-dimethyl-phosphineoxide and 0.2g of sodium iodide, the reaction mixture was heated for 2 hours to C,filtered and the solvent was then removed by filtration under reducedpressure. The residue was extracted several times with chloroform; thecombined chloroform solutions were clarified with charcoal, concentratedand allowed to crystallize after addition of petroleum ether. The 7-chloro-l-(dimethylphosphinylmethyl)-5-phenyll ,2,4,5-tetrahydro-3H-l,S-benzodiazepine-Z,4-dione (melting point 255 257 C) obtained in thismanner could be purified by renewed recrystallization from a mixture oftoluene and methanol or chloroform and petroleum ether.

Yield: 26.9 g (71 percent of the theory) of colorless crystals. Meltingpoint 257 25 8 C.

b. 14.4 g (0.05 mole) of 7-chloro-5-phenyl-l,2,4,5- tetrahydro-SH-l,5-benzodiazepine-2,4-dione in 200 ml of dimethylformamide wereconverted as described under a) with 2.5 g of sodium hydride (50 percentstrength in oil) into the sodium salt and the latter was combined with9.5 g of methane-sulfonic aciddimethylphosphinyl-methyl ester. Afterhaving heated the whole for 3 hours to about 100 C, the solvent wasremoved under reduced pressure and the residue was worked up asdescribed under (a).

Yield: 12.4 g (66% of the theory) of 7-chloro-l-(dimethylphosphinylmethyl )-5 -phenyl-l ,2,4,5- tetrahydro-l,S-benzodiazepine-Z,4-dione; point 257 258 C.

c. 13.3 g of N-(2-amino-5-chlorophenyl)-N-phenylmalonic acid ethyl esteramide were introduced in portions, while stirring, at room temperature,into a sodium ethylate solution of 160 ml of absolute ethanol and 1.2 gof sodium. After having stirred the whole at 20 25 C for 3 hours, thereaction mixture was combined with 6.6 g ofchloromethyl-dimethyl-phosphine oxide and heated for 6 hours underreflux. The content of the flask was then poured into a great amount ofwater and melting the aqueous solution was extracted several times withmethylene chloride after having been clarified with charcoal. The7-chloro-l-(dimethyl-phospinylmethyl)- S-phenyl-l ,2,4,5-tetrahydro-3H-l,Sbenzodiazepine- 2,4-dione which remained behind after evaporation ofthe methylene chloride was purified as described under a). Melting point257 258 C.

We claim: 1. A compoundpf the formulal 0 T 2)r (R)z in which Rrepresents an alkyl group having one to three carbon atoms, R, and R,which may be identical or different, represent a hydrogen atom or ahalogen atom, the trifluoromethyl or nitro group, or an alkoxy grouphaving one to two carbon atoms, R represents a hydrogen atom or an alkylgroup having one to three carbon atoms, and n represents a number from 1to 3.

2. The compound defined in claim 1 wherein R is CH,, R R and R arehydrogen, and n is l.

3. The compound defined in claim 1 wherein R is CH R is chlorosubstituted in the 7-position, R and R are hydrogen and 1% 1.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,7l8,6L5 Dated February 27, 1973 Inventor-(s) Heinz Kuch et 8.1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In heading, Item [30], change the date of German Application P 21 18262.7 from "April 15, 1970" to "April 15,1971".

Signed and sealed this 11th day of June 1974.

. (SEAL) A-fiest:

EDWARD MLFLETCHERJR.

C. MARSHALL DANN Attesting Officer Commissioner of Patents F ORM PO-105O(10-69) USCOMNl-DC 6O3'l6-P69 us. GOVERNMENT PRINTING OFFICE l9"o-ail-su,

2. The compound defined in claim 1 wherein R is CH3, R1, R2 and R3 arehydrogen, and n is
 1. 3. The compound defined in claim 1 wherein R isCH3, R1 is chloro substituted in the 7-position, R2 and R3 are hydrogenand n is 1.